There was clear evidence of hepatocarcinogenic activity in B6C3F1 mice following 2 years of tetrafluoroethylene (TFE) exposure. The present study was designed to characterize the H- and K-ras oncogenes in liver neoplasms induced in mice exposed to 0, 312, 625 or 1250 ppm TFE. Ras mutations were identified by restriction fragment length polymorphism, single strand conformation polymorphism analysis and direct sequencing of PCR amplified DNA isolated from frozen or paraffin-embedded liver neoplasms. A low frequency (15% 9/59) of H-ras codon 61 mutation was detected in hepatocellular neoplasms when compared to the high frequency (59% of this study and 56% of historical data) in spontaneous liver neoplasms. There was no difference in the mutation frequency and spectrum among exposure groups or between benign and malignant hepatocellular neoplasms. K-ras mutations at codons 12, 13 and 61 were not detected in hepatocellular neoplasms. These data suggest that TFE-induced hepatocellular neoplasms develop by pathways mostly independent of ras activation, and that are different from those of spontaneous liver neoplasms.